CN107879919A - A kind of preparation method of the heptadione of medicine intermediate 3,5 - Google Patents
A kind of preparation method of the heptadione of medicine intermediate 3,5 Download PDFInfo
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- CN107879919A CN107879919A CN201810020234.0A CN201810020234A CN107879919A CN 107879919 A CN107879919 A CN 107879919A CN 201810020234 A CN201810020234 A CN 201810020234A CN 107879919 A CN107879919 A CN 107879919A
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
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Abstract
The invention provides a kind of preparation method of the heptadione of medicine intermediate 3,5, methods described includes：Raw material butanone and methyl propionate, in organic solvent, in the presence of base catalyst, reaction obtains 3,5 heptadione, this method can effectively improve the selectivity and reaction yield of 3,5 heptadione, and reaction yield can reach 72.4%, the difficulty of post-reaction treatment is reduced simultaneously, the pollution to environment is reduced, reduces production cost, improves the economic efficacy and security of production.
Description
Technical field
The present invention relates to a kind of preparation method of medicine intermediate dione compounds, more particularly to it is a kind of in high yield
Beta-diketone compound preparation method.
Background technology
Beta-diketone compound is a kind of important compound, and it is frequently as the important synthesis unit in organic synthesis to build
Other medicines compound or functional material.Beta-diketone compound is also a kind of compound with extensive use, such as can be used
In METAL EXTRACTION and polymer stabilising.Therefore, the synthetic methods of the cyclohexadione compounds great reality in pharmaceutical production is studied
Meaning, there is very big value to chemical and field of medicaments.
Method using Claisen condensation is the generally known method for preparing beta-diketone compound.
3,5- heptadione are important beta-diketone compounds, and 3,5- heptadione are synthesis 3, and the key of 5- heptandiols is middle
Body.Oneself has the method that document report prepares 3,5- heptadione, but this method yield is relatively low, and production operability is not strong.Its
In, ZhurnalObshcheiKhimil, 28,2845 ~ 6,1958 report malonyl chloride and grignard reagent E tMgBr is anti-
The 3,5- heptadione products that yield is 51% should be obtained.This method must react under -70 DEG C of extremely low temperature, and handle non-
It is often difficult, it is difficult to realize in industrial practice.
CN1636422A is reported by using Claisen condensation method, makees catalyst with potassium tert-butoxide, using DMF as solvent system
Standby 2,2,6,6- tetramethyl -3,5 heptadione, yield 52%.CN1805916A, which is disclosed, prepares 2,6- dimethyl -3,5- heptan
Diketone, it, by the use of potassium tert-butoxide as catalyst, prepares 3,5- heptadione, yield is 45% under DMF solvent system.
Document J. Am .Chem.soc, 27,1036 (1 962) are reported by the use of NaH as catalyst preparation 2, and 2,6,
6- tetramethyl -3,5- heptadione, reaction yield are relatively low.
J.Org.Chem. 50,26,1985,5598 ~ 5604 preparation 3,5- heptadione are reported.The document is reported, with four
Hydrogen furans is solvent, and under the catalytic action of sodium hydride, ethyl propionate is condensed with MEK, obtains 3,5 heptadione crude products,
Copper acetate and 3 is recycled, 5 heptan, two intoxicated soft-shelled turtles closed to obtain complex, filtered, and purification, obtained 3,5 heptadione products.In this article
It is ethyl propionate to offer middle report ethyl propionate and the mol ratio of fourth reward:Butanone=1:1. 03, ethyl propionate and sodium hydride rub
Your ratio is ethyl propionate:Sodium hydride=1: 1. 95 .However, because substantial amounts of sodium hydride is present, in actual production, due to big
The sodium hydride unreacted of amount is complete, thus there is danger.In addition, substantial amounts of high content organic wastewater environment is caused it is unfavorable
Influence, and the cost for producing 3,5 heptadione is also very high.
As can seen above, beta-diketone compound has extensive purposes in chemical and field of medicaments, in prior art
In, substantial amounts of enterprise and institute have carried out in-depth study to it, however, for being capable of the technique of actual production and
Speech, many problems of generally existing, such as the yield of reaction are relatively low, and it is not high enough to react the purity of products obtained therefrom, in course of reaction
Dangerous destabilizing factor be present, waste has larger pollution to environment caused by reaction.Therefore, it is still anxious in industrial and industry
A kind of modified preparation technology for problem above need to be provided.
The content of the invention
In view of the above-mentioned problems existing in the prior art, the invention provides a kind of reaction yield and feed stock conversion height, production
Product purity is high, the method for preparing medicine intermediate beta-diketone compound that reaction safety is good and environmental pollution is small.
Technical teaching for solving the problem was
Applicant is had found by the further investigation to correlation technique:During Claisen condensation, highly basic work is generally required
For the catalyst of reaction, highly basic of the prior art is mainly inorganic strong alkali, such as Sodamide, sodium hydride, sodium tert-butoxide, tertiary fourth
Potassium alcoholate, sodium methoxide, potassium methoxide, caustic alcohol, potassium ethoxide etc., solvent used are mainly organic inert solvent, such as toluene, chlorine
Benzene, alcohol, aliphatic ether or DMF etc., because dissolubility of the above-mentioned inorganic strong alkali catalyst in organic inert solvent is poor, cause to urge
The ability of change reaction is relatively low, and the selectivity of reaction can also be deteriorated therewith, such as the reaction of methyl propionate and 2- butanone prepares 3,5-
During heptadione, because dissolubility of the catalyst in inert organic solvents is poor, alkali catalyst is caused to activate 2-
1 and the reactive hydrogen of 3 in butanone, so as to obtain more accessory substance and increase the separating difficulty of reaction.
Based on above-mentioned analysis, the invention provides the preparation method of one kind 3,5- heptadione compounds, described method bag
Include：Raw material butanone and propionic ester, in organic solvent, in the presence of base catalyst, reaction obtains 3,5- heptadione.
Preferably, described organic solvent is inert organic solvents, more preferably benzene, toluene, chlorobenzene, alcohol, fat
Ether or DMF, described aliphatic ether are ether, methyl isopropyl ether, methyl tertiary butyl ether(MTBE), glycol dimethyl ether etc.；It is further excellent
Elect methyl isopropyl ether, methyl tertiary butyl ether(MTBE) as, be still more preferably methyl tertiary butyl ether(MTBE), inertia of the present invention has
Solvent will not both carry out proton transfer reaction, also solvation not occur with solute.
Preferably, described propionic ester is methyl propionate or ethyl propionate or propyl propionate.
Preferably, described base catalyst is Sodamide, sodium hydride and sodium alkoxide, and described sodium alkoxide is sodium methoxide, methanol
Potassium, caustic alcohol, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide etc., preferably sodium tert-butoxide and potassium tert-butoxide, the more preferably tert-butyl alcohol
Potassium.
During ester is added, generated 3,5- heptadione is removed by distilling typically under the conditions of solvent refluxing
Compound.Therefore the method reaction temperature of the Claisen condensation is preferably higher than the boiling point of the alcohol at least 15 DEG C.Reaction temperature is at least
30℃.In a kind of particularly suitable embodiment of the present invention, range of reaction temperature is 35 DEG C to 200 DEG C, with 40 DEG C to 150
DEG C preferably, pressure is normal pressure.Pressure is not not extremely important for this method, but selects specified pressure can be to a certain degree
The quick removal of caused product dione compounds in upper promotion reaction medium.If reaction is carried out under reduced pressure, conveniently
Reaction temperature model because 30 DEG C to 140 DEG C.
The mol ratio of butanone and propionic ester is preferably less than 1, preferably 1:1.1-5 more preferably 1:1.2-4.Generally, ester than
Ketone excess 10-300%.
In terms of existing technologies, acquirement has the beneficial effect that the present invention：
1st, present invention employs specific catalyst potassium tert-butoxide and specific reaction dissolvent methyl tertiary butyl ether(MTBE), due to the tert-butyl alcohol
The organic group of potassium is larger can be preferably among solvent, and methyl tertiary butyl ether(MTBE) has relatively large polarity, can be preferable
Ground catalyst-solvent potassium tert-butoxide, and reaction raw materials assimilation compound and ester compounds also can be preferably dissolved, so as to improve
The homogeneity of reaction system, avoid in reaction system because deliquescent problem, so as to produce a large amount of accessory substances, effectively carry
The high selectivity and reaction yield of product, reaction yield can reach 72.4%, while reduce the difficulty of post-reaction treatment,
The pollution to environment is reduced, greatly reduces production cost, improves the economic efficacy of production.
2nd, due to reaction used by catalyst be potassium tert-butoxide, avoid Sodamide used in the prior art, hydrogen
Change the catalyst of the highly dangerous such as sodium, improve the security of production, reduce the requirement to consersion unit etc., so as to drop
The cost of low production.
3rd, the present invention is improved by the optimization to reaction condition, reaction yield, and the reaction time substantially shortens, and is had very
High industrial productivity.
Embodiment
The preparation technology of the present invention is further described below by way of exemplary embodiment.But these embodiments are only
For illustrating the present invention, any restrictions are not formed to the scope of the present invention.It will be apparent to a skilled person that not
In the case of deviateing the spirit and scope of the present invention, technical scheme and its embodiment can be carried out a variety of
Equivalence modification, replace and change, these all should fall within the scope of protection of the present invention.
Embodiment 1
In three-necked flask, by 11.2g potassium tert-butoxides（0.1mol）Add in 50mL anhydrous methyl tertbutyl ethers, heating stirring is returned
Stream 30 minutes, cools to 35 DEG C, 0.3mol methyl propionates and 0.1mol butanone is slowly added drop-wise in reaction bulb successively, added
Reaction 2 hours after complete.Then room temperature is cooled to, 30mL water is added dropwise under the protections of N 2, adjusts pH value neutral with watery hydrochloric acid, reaction solution
Stratification, organic layer is separated, to organic layer knowable to gas-chromatography is analyzed, product 3, the reaction yield of 5- heptadione is
72.4%（In terms of butanone）.
Embodiment 2
In three-necked flask, by 11.2g potassium tert-butoxides（0.1mol）Add in 50mL absolute ethers, heating stirring flows back 30 points
Clock, 35 DEG C are cooled to, 0.3mol methyl propionates and 0.1mol butanone are slowly added drop-wise in reaction bulb successively, reacted after adding
2 hours.Then room temperature is cooled to, 30mL water is added dropwise under the protections of N 2, adjusts pH value neutral with watery hydrochloric acid, reaction solution standing point
Layer, separates organic layer, and to organic layer knowable to gas-chromatography is analyzed, product 3, the reaction yield of 5- heptadione is 44.6%
（In terms of butanone）.
Embodiment 3
In three-necked flask, by 11.2g potassium tert-butoxides（0.1mol）Add in the anhydrous diethylene glycol dimethyl ethers of 50mL, heating stirring
Backflow 30 minutes, cools to 35 DEG C, 0.3mol methyl propionates and 0.1mol butanone is slowly added drop-wise in reaction bulb successively,
Reacted 2 hours after adding.Then room temperature is cooled to, 30mL water is added dropwise under the protections of N 2, adjusts pH value neutral with watery hydrochloric acid, reaction
Liquid stratification, separates organic layer, to organic layer knowable to gas-chromatography is analyzed, product 3, and the reaction yield of 5- heptadione
For 62.3%（In terms of butanone）.
Embodiment 4
In three-necked flask, by 11.2g potassium tert-butoxides（0.1mol）Add in 50mL dry ethylene glycol dimethyl ethers, heating stirring is returned
Stream 30 minutes, cools to 35 DEG C, 0.3mol methyl propionates and 0.1mol butanone is slowly added drop-wise in reaction bulb successively, added
Reaction 2 hours after complete.Then room temperature is cooled to, 30mL water is added dropwise under the protections of N 2, adjusts pH value neutral with watery hydrochloric acid, reaction solution
Stratification, organic layer is separated, to organic layer knowable to gas-chromatography is analyzed, product 3, the reaction yield of 5- heptadione is
58.7%（In terms of butanone）.
Embodiment 5
In three-necked flask, by 11.2g potassium tert-butoxides（0.1mol）Adding in 50mL anhydrous benzenes, heating stirring flows back 30 minutes,
35 DEG C are cooled to, 0.3mol methyl propionates and 0.1mol butanone are slowly added drop-wise in reaction bulb successively, react 2 after adding
Hour.Then room temperature is cooled to, 30mL water is added dropwise under the protections of N 2, adjusts pH value neutral with watery hydrochloric acid, reaction solution stratification,
Organic layer is separated, to organic layer knowable to gas-chromatography is analyzed, product 3, the reaction yield of 5- heptadione is 38.9%（With
Butanone meter）.
Embodiment 6
In three-necked flask, by 11.2g potassium tert-butoxides（0.1mol）Add in 50mL dry DMFs, heating stirring flows back 30 points
Clock, 35 DEG C are cooled to, 0.3mol methyl propionates and 0.1mol butanone are slowly added drop-wise in reaction bulb successively, reacted after adding
2 hours.Then room temperature is cooled to, 30mL water is added dropwise under the protections of N 2, adjusts pH value neutral with watery hydrochloric acid, reaction solution standing point
Layer, separates organic layer, and to organic layer knowable to gas-chromatography is analyzed, product 3, the reaction yield of 5- heptadione is 46.2%
（In terms of butanone）.
Embodiment 7
In three-necked flask, by 9.6g sodium tert-butoxides（0.1mol）Add in 50mL anhydrous methyl tertbutyl ethers, heating stirring is returned
Stream 30 minutes, cools to 35 DEG C, 0.3mol methyl propionates and 0.1mol butanone is slowly added drop-wise in reaction bulb successively, added
Reaction 2 hours after complete.Then room temperature is cooled to, 30mL water is added dropwise under the protections of N 2, adjusts pH value neutral with watery hydrochloric acid, reaction solution
Stratification, organic layer is separated, to organic layer knowable to gas-chromatography is analyzed, product 3, the reaction yield of 5- heptadione is
60.8%（In terms of butanone）.
Embodiment 8
In three-necked flask, by 8.4g potassium ethoxides（0.1mol）Add in 50mL anhydrous methyl tertbutyl ethers, heating stirring backflow
30 minutes, 35 DEG C are cooled to, 0.3mol methyl propionates and 0.1mol butanone are slowly added drop-wise in reaction bulb successively, added
React 2 hours afterwards.Then room temperature is cooled to, 30mL water is added dropwise under the protections of N 2, adjusts pH value neutral with watery hydrochloric acid, reaction solution is quiet
Layering is put, separates organic layer, to organic layer knowable to gas-chromatography is analyzed, product 3, the reaction yield of 5- heptadione is
52.6%（In terms of butanone）.
Embodiment 9
In three-necked flask, by 2.4g sodium hydrides（0.1mol）Add in 50mL anhydrous methyl tertbutyl ethers, heating stirring backflow
30 minutes, 35 DEG C are cooled to, 0.3mol methyl propionates and 0.1mol butanone are slowly added drop-wise in reaction bulb successively, added
React 2 hours afterwards.Then room temperature is cooled to, 30mL water is added dropwise under the protections of N 2, adjusts pH value neutral with watery hydrochloric acid, reaction solution is quiet
Layering is put, separates organic layer, to organic layer knowable to gas-chromatography is analyzed, product 3, the reaction yield of 5- heptadione is
46.%（In terms of butanone）.
Embodiment 10
In three-necked flask, by 3.9g Sodamides（0.1mol）Add in 50mL anhydrous methyl tertbutyl ethers, heating stirring backflow
30 minutes, 35 DEG C are cooled to, 0.3mol methyl propionates and 0.1mol butanone are slowly added drop-wise in reaction bulb successively, added
React 2 hours afterwards.Then room temperature is cooled to, 30mL water is added dropwise under the protections of N 2, adjusts pH value neutral with watery hydrochloric acid, reaction solution is quiet
Layering is put, separates organic layer, to organic layer knowable to gas-chromatography is analyzed, product 3, the reaction yield of 5- heptadione is
48.7%（In terms of butanone）.
The reaction yield situation of the different catalysts of table 1 and inert organic solvents
| Catalyst | Inert organic solvents | Reaction yield（%） |
| Potassium tert-butoxide | Methyl tertiary butyl ether(MTBE) | 72.4 |
| Potassium tert-butoxide | Ether | 44.6 |
| Potassium tert-butoxide | Diethylene glycol dimethyl ether | 62.3 |
| Potassium tert-butoxide | Glycol dimethyl ether | 58.7 |
| Potassium tert-butoxide | Benzene | 38.9 |
| Potassium tert-butoxide | DMF | 46.2. |
| Sodium tert-butoxide | Methyl tertiary butyl ether(MTBE) | 60.8 |
| Potassium methoxide | Methyl tertiary butyl ether(MTBE) | 52.6 |
| Sodium hydride | Methyl tertiary butyl ether(MTBE) | 46.3 |
| Sodamide | Methyl tertiary butyl ether(MTBE) | 48.7 |
By table 1 it can be found that catalyst potassium tert-butoxide is in the presence of methyl tert-butyl ether solvent, product 3,5- heptadione
Product yield highest can reach 72.4%, reason be probably due to dissolubility of the organic catalyst in organic inert solvent compared with
Difference, the local concentration of catalyst is too high, and raw material 2- butanone, methyl propionate and product 3, exists in 5- heptandiols at least one
Reactive hydrogen, that is, different accessory substances may be produced in reacting, therefore, higher selectivity can be obtained to this in initial reaction stage
Reaction is directly perceived important, and creatively selection solves this well with the combination of potassium tert-butoxide and methyl tertiary butyl ether(MTBE) in the present invention
Problem, the selectivity and product yield of reaction are greatly improved.
The preferred embodiment of the present invention described in detail above, still, the present invention are not limited in above-mentioned embodiment
Detail, in the range of the technology design of the present invention, a variety of simple variants can be carried out to technical scheme, this
A little simple variants belong to protection scope of the present invention.
It is further to note that each particular technique feature described in above-mentioned embodiment, in not lance
In the case of shield, it can be combined by any suitable means.
In addition, various embodiments of the present invention can be combined randomly, as long as it is without prejudice to originally
The thought of invention, it should equally be considered as content disclosed in this invention.
Claims (10)
1. a kind of medicine intermediate 3, the preparation method of 5- heptadione, methods described include：Raw material butanone and propionic ester, organic
In solvent, in the presence of base catalyst, reaction obtains 3,5- heptadione, it is characterised in that：Described organic solvent is lazy
Property organic solvent, more preferably benzene, toluene, chlorobenzene, alcohol, aliphatic ether or DMF, described aliphatic ether is that ether, methyl are different
Propyl ether, methyl tertiary butyl ether(MTBE), diethylene glycol dimethyl ether or glycol dimethyl ether etc.；Described base catalyst is Sodamide,
One or more in sodium hydride or alkoxide.
A kind of 2. preparation method of beta-diketone compound according to claim 1, it is characterised in that:Described propionic ester is
Methyl propionate or ethyl propionate or propyl propionate.
A kind of 3. preparation method of beta-diketone compound according to claim 1, it is characterised in that:The charging sequence of reaction
For base catalyst is added in inert organic solvents, propionic ester and butanone are then sequentially added.
A kind of 4. preparation method of beta-diketone compound according to claim 1, it is characterised in that:The inertia is organic molten
Agent will not both carry out proton transfer reaction, also solvation not occur with solute.
A kind of 5. preparation method of beta-diketone compound according to claim 1, it is characterised in that:Described inertia is first
Base isopropyl ether or methyl tertiary butyl ether(MTBE), preferably methyl tertiary butyl ether(MTBE).
A kind of 6. preparation method of beta-diketone compound according to claim 1, it is characterised in that：Described alkoxide is first
Potassium alcoholate, caustic alcohol, potassium ethoxide, sodium tert-butoxide or potassium tert-butoxide etc., preferably sodium tert-butoxide or potassium tert-butoxide, more preferably tertiary fourth
Potassium alcoholate.
A kind of 7. preparation method of beta-diketone compound according to claim 1, it is characterised in that：Described base catalysis
The mol ratio of agent and butanone is 1:1-3, preferably 1:1-1.5.
8. according to a kind of preparation method of any described beta-diketone compounds of claim 1-5, it is characterised in that：Described alcohol
Salt potassium tert-butoxide, described inert organic solvents are methyl tertiary butyl ether(MTBE).
A kind of 9. preparation method of beta-diketone compound according to claim 1, it is characterised in that:Reaction temperature is at least
For 30 DEG C, preferable reaction temperature scope is 35 DEG C to 200 DEG C, and pressure is normal pressure.
A kind of 10. preparation method of beta-diketone compound according to claim 1, it is characterised in that:Butanone and propionic ester
Mol ratio be less than 1, preferably 1:1.1~5.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1031366A (en) * | 1987-07-18 | 1989-03-01 | 北京市化工研究院 | The manufacture method of beta-diketone compounds |
| EP0454624A1 (en) * | 1990-04-26 | 1991-10-30 | Ciba-Geigy Ag | Process for the production of 1,3-diketones |
| CN107324985A (en) * | 2016-04-29 | 2017-11-07 | 中国石油化工股份有限公司 | A kind of preparation method of beta-diketone compound |
-
2018
- 2018-01-09 CN CN201810020234.0A patent/CN107879919A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1031366A (en) * | 1987-07-18 | 1989-03-01 | 北京市化工研究院 | The manufacture method of beta-diketone compounds |
| EP0454624A1 (en) * | 1990-04-26 | 1991-10-30 | Ciba-Geigy Ag | Process for the production of 1,3-diketones |
| CN107324985A (en) * | 2016-04-29 | 2017-11-07 | 中国石油化工股份有限公司 | A kind of preparation method of beta-diketone compound |
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